The focus of this competitive renewal application is on monocytes driving CNS disease in the central nervous system (CNS) in neuroAIDS. In the previous funding period, we defined the role of CDS lymphocytes controlling the development of SIV encephalitis (SIVE), developed a model of rapid and consistent CNS disease of neuroAIDS, and demonstrated an increase of activated and infected monocytes that correlate with neuronal injury demonstrated by MR spectroscopy. Antiretroviral therapy that slightly decreased plasma virus, rapidly reversed monocyte activation and neuronal injury. Our focus in the upcoming funding period is to identify specific monocyte subsets that correlate with neuronal injury and recovery following immune- or monocyte-targeted therapy. We hypothesize that specific subsets of monocytes expand with and drive CNS disease, and decrease with immune modulators directly targeting monocytes or monocyte traffic. We propose 3 specific aims to study our hypothesis. Studies in aim 1 will selectively identify immune- phenotypically and functionally distinct monocyte subsets expanded in SIV infected animals with neuroAIDS and define factors regulating their expansion. Studies in aim 2 propose to use leukapheresis, in normal and SIV infected animals to directly assess the role of specific monocyte subsets to traffic to the CNS in normal, viremic and SIV infected animals with CNS disease. Studies in aim 3 proposed to use monoclonal antibodies against VLA-4 and VLA-1, and a pharmacologic inhibitor of polyamine synthesis that selectively targets CD 14+ CD 16+ monocytes to determine the role of active monocyte traffic contributing to ongoing neuronal injury in neuroAIDS.